The Glycine Receptor Allosteric Ligands Library (GRALL)

Abstract

Motivation Glycine receptors (GlyRs) mediate fast inhibitory neurotransmission in the brain and have been recognized as key pharmacological targets for pain. A large number of chemically diverse compounds that are able to modulate GlyR function both positively and negatively have been reported, which provides useful information for the development of pharmacological strategies and models for the allosteric modulation of these ion channels. Results Based on existing literature, we have collected 218 unique chemical entities with documented modulatory activities at homomeric GlyR-α1 and -α3 and built a database named GRALL. This collection includes agonists, antagonists, positive and negative allosteric modulators and a number of experimentally inactive compounds. Most importantly, for a large fraction of them a structural annotation based on their putative binding site on the receptor is provided. This type of annotation, which is currently missing in other drug banks, along with the availability of cooperativity factors from radioligand displacement experiments are expected to improve the predictivity of in silico methodologies for allosteric drug discovery and boost the development of conformation-based pharmacological approaches. Availability and implementation The GRALL library is distributed as a web-accessible database at the following link: https://ifm.chimie.unistra.fr/grall. For each molecular entry, it provides information on the chemical structure, the ligand-binding site, the direction of modulation, the potency, the 3D molecular structure and quantum-mechanical charges as determined by our in-house pipeline. Contact mcecchini@unistra.fr Supplementary information Supplementary data are available at Bioinformatics online.

Attenuation of clinical and immunological outcomes during SARS‐CoV‐2 infection by ivermectin

“…Considerable sex differences are observed in terms of clinical presentation, inflammatory profile, and transcriptomic signatures in the lungs of hamsters, as seen in COVID‐19 human patients, where men tend to develop more severe disease than women (Jin et al , 2020 ; Takahashi et al , 2020 ), possibly in relation with androgen signaling (vom Steeg & Klein, 2019 ; Samuel et al , 2020 ; Scully et al , 2020 ). Interestingly, sex steroids, here female hormones, might also influence both the course of COVID‐19 in hamsters and the effects of IVM, possibly due to the potentiation of cell receptors signaling in females, such as nAChRs (Krause et al , 1998 ; Cross et al , 2017 ) and GlyRs (Van Den Eynden et al , 2009 ; Cerdan et al , 2020 ), of which IVM is a positive allosteric modulator.…”

Nicotinic receptors: From protein allostery to computational neuropharmacology

“…In addition, their binding sites have not been evolved for function and are potentially more druggable; reviewed in (Changeux and Christopoulos, 2016). Recent structural analyses on the glycine receptor anionic channel (GlyR) have revealed the location of (at least) seven distinct allosteric sites, which span the entire receptor structure and are located mostly at the subunit-subunit interfaces including the ion transmembrane pore (Cerdan et al, 2020). In the most recent cryo-EM structure of the cationic nAChR α7 solved in the presence of PNU-120596, this potent and selective PAM was found to bind to the transmembrane domain of the receptor at the interface of adjacent subunits (Zhao et al, 2021).…”

“…In light of this, the availability of automated implementations of rigorous binding free energy methods in combination with enhanced sampling strategies, and/or conformational free energy calculations in the apo state of the receptor offer an exciting prospective towards the establishment of a computational neuropharmacology of brain receptors. In addition, the increasing availability of specialized datasets of ligands with known modulatory activities at pentameric receptors such as GRALL (Cerdan et al, 2020), which includes a large number of agonists, antagonists, positive and negative allosteric modulators at GlyR α1 with a structural annotation of their putative binding site, or ACRALL (Brando, Cerdan, Changeux, Cecchini) with approximately 5000 modulatory compounds targeting two brain nAChRs (α7 and α4β2) and the muscle-type nAChR (2αβγδ) emerge as invaluable resources for calibration and validation.…”

Rational design of allosteric modulators: Challenges and successes

“…Recently, a web database named GRALL was designed containing all allosteric ligands that modulate the GlyR‐α1 and GlyR‐α3 function, providing information on their putative binding sites, the direction of modulation, the potency, and others 198 . This database is expected to be a significant asset in the structure‐based allosteric drug discovery of GlyRs.…”